Coordinate regulation of the WNT and Hippo pathways by the novel Ras effector NORE1A.

Ras is the most frequently activated oncogene found in human cancer, but its mechanisms of action remain only partially understood. Ras activates multiple signaling pathways in order to promote transformation, but can also exhibit a potent ability to induce growth arrest and death. NORE1A (RASSF5) is a direct Ras effector that acts as a tumor suppressor promoting senescence and apoptosis. Its expression is frequently lost in human tumors and its mechanism of action remains unclear. Here I show that NORE1A forms a direct, Ras regulated, complex with β-TrCP, the substrate recognition component of the SCF-β-TrCP ubiquitin ligase complex. NORE1A also binds GSK-3β resulting in enhanced kinase activity, which is required to phosphorylate SCF-β-TrCP substrates before their recognition by the ubiquitin ligase complex. Thus, by acting as a scaffold between β-TrCP and GSK-3β, NORE1A allows for Ras to both qualitatively and quantitatively enhance the proteosomal degradation of SCF-β-TrCP targets, such as β- catenin and TAZ. However, this control is substrate specific, as IκB, another substrate of SCF-β-TrCP, is not sensitive to NORE1A promoted degradation. Thus, I identify a completely novel signaling mechanism for Ras that allows the coordinate regulation of the Wnt/β-catenin and Hippo pathways, and potentially multiple other SCF-β-TrCP targets. The mechanism is frequently impaired in tumors by loss of NORE1A expression and provides an explanation for the observation that β-TrCP can act as a tumor suppressor or an oncogene in different cell systems

Ghost-free completion of an effective matter coupling in bimetric theory

We consider a particular set of ghost-free interactions for three spin-2 fields in which we freeze out the dynamics of the metric tensor that couples to the matter sector. Integrating out the non-dynamical degrees of freedom in vacuum results in a ghost-free bimetric theory. In the presence of the matter source, which we treat as a small perturbation, the equations for the non-dynamical field can be solved perturbatively for its vierbein. This results in ghost-free bimetric theory in vierbein formulation with a modified matter coupling. To lowest order in matter perturbations, we precisely obtain an effective matter coupling that has been suggested earlier in the literature. This coupling contains a linear combination of the two vierbeine whose corresponding metric fluctuation coincides with the massless spin-2 mode. In the past, bimetric theory with this symmetric coupling has been treated as an effective theory valid at low energies without a ghost-free completion. Our results demonstrate that the effective matter coupling can be rendered entirely ghost-free by including the higher-order corrections obtained from the trimetric setup.Comment: 15 pages, fixed typo in equation (4.6

Ghost-free completion of an effective matter coupling in bimetric theory

We consider a particular set of ghost-free interactions for three spin-2 fields in which we freeze out the dynamics of the metric tensor that couples to the matter sector. Integrating out the non-dynamical degrees of freedom in vacuum results in a ghost-free bimetric theory. In the presence of the matter source, which we treat as a small perturbation, the equations for the non-dynamical field can be solved perturbatively for its vierbein. This results in ghost-free bimetric theory in vierbein formulation with a modified matter coupling. To lowest order in matter perturbations, we precisely obtain an effective matter coupling that has been suggested earlier in the literature. This coupling contains a linear combination of the two vierbeine whose corresponding metric fluctuation coincides with the massless spin-2 mode. In the past, bimetric theory with this symmetric coupling has been treated as an effective theory valid at low energies without a ghost-free completion. Our results demonstrate that the effective matter coupling can be rendered entirely ghost-free by including the higher-order corrections obtained from the trimetric setup.Comment: 15 pages, fixed typo in equation (4.6

Bimetric cosmology is compatible with local tests of gravity

Recently, Kenna-Allison et.al. claimed that bimetric gravity cannot give rise to a viable cosmological expansion history while at the same time being compatible with local gravity tests. In this note we review that claim and combine various results from the literature to provide several simple counter examples. We conclude that the results of Kenna-Allison et.al. cannot hold in general.Comment: 6 pages, 2 figure

Theoretical Investigation of the Effects of the Artificial-Feel System on the Maneuvering Characteristics of the F-89 Airplane

The possibility of overshooting the anticipated normal acceleration as a result of the artificial-feel characteristics of the F-89C airplane at a condition of minimum static stability was investigated analytically by means of an electronic simulator. Several methods of improving the stick-force characteristics were studied. It is shown that, due to the lag in build-up of the portion of the stick force introduced by the bobweight, it would be possible for excessive overshoots of normal acceleration to occur in abrupt maneuvers with reasonable assumed control movements. The addition of a transient stick force proportional to pitching acceleration (which leads the normal acceleration) to prevent this occurring would not be practical due to the introduction of an oscillatory mode to the stick-position response. A device to introduce a viscous damping force would Improve the stick-force characteristics so that normal acceleration overshoots would not be likely, and the variation of the maximum stick force in rapid pulse-type maneuvers with duration of the maneuver then would have a favorable trend

A Multifunctional Characterization Test Bench for Shape Memory Alloy Micro-Wires : Design, Implementation and Validation

Most relevant to predicting the behavior of shape-memory-alloy (SMA)-based actuatorsensor applications activated by Joule heating are the electro-mechanical characteristics of the material under consideration. For a comprehensive characterization, a single setup that is able to provide all relevant data and information is desirable. This work covers the design, implementation and validation of such a high-end test bench for the holistic characterization of SMA micro-wires. In addition, the setup provides the possibility of application simulation experiments. Key elements of the design are the clamping mechanism guided on air bearings, a linear direct drive, a high-resolution load cell, a high-precision constant current source and a stress-controlled in-line wire sample installation. All measurements take place inside an isolated, temperature-controlled chamber. With the presented setup, the electro-mechanical and thermal characteristics of SMA wire samples with diameters from 20 µm to 100 µm can be determined. Via hardware-in-the-loop (HiL) implementation, the outputs with different biasing mechanisms and additional end-stops can be simulated even at high ambient temperatures. The generated results facilitate the prediction of the exact characteristics of SMA-driven actuator-sensor systems in a variety of applications and lead to a better general understanding of the alloy’s properties. All functionalities and features of the setup are presented by discussing the results of exemplary experiments

Product Generation Module: Automated Production Planning for optimized workload and increased efficiency in Matrix Production Systems

Ever increasing demand for individualized and customized products induce the need for high variability in production and manufacturing through Mass Customisation. Mass Customisation requires more flexibility and adaptability capabilities in production systems. Matrix Production is a tact free job-shop like production system enabling variable production routing through a matrix shaped layout of partially redundant machines. Hence, it is one way to increase a production system’s flexibility and adaptability. A more powerful production control system comes hand in hand with the evolution towards a tact free Matrix Production System. However, the additional degree of freedom due to the flexibility not only touches production control, but also production planning, thus enabling the production of portfolio external products. Implementation of a Product Generation Module optimizes the workload of Matrix Production Systems to increase their efficiency by assessing the suitability of co-production of portfolio external products. Generation of suitable production orders increase machine utilization without impeding the original multi-dimensional production goals. Thus, reaching new production strategies that include the creation of value through effective manipulation of minor products and byproducts. The flexibility of Matrix Production Systems acts as the Product Generation Modules enabler, insofar as flexibility is the ability of a system to perform within an acceptable production corridor without layout and planning adjustments. This can be enhanced by making use of the Matrix Production Systems adaptability to increase the set of portfolio external products through layout and planning adjustments. Hence, this strategy leads to a continuous automated planning phase and additional revenue due to the additional manufacture of minor products within a Matrix Production System. Doing so allows the Matrix Production System to react towards external demand related and internal capacity related events without sacrificing precious value creation opportunities

Testing of a Multiple Criteria Assessment Tool for Healthcare Facilities Quality and Sustainability: The Case of German Hospitals

Background: Hospital facilities are an essential part of healthcare systems, making the assessment of their quality and sustainability pivotal. Most existing evaluation tools lack a holistic and validated approach, while predominantly excluding the built environment. The Italian hospital evaluation tool SustHealth v2 addresses the shortcoming of existing applications through its structured and more integrated approach; there is the need for further testing it. Methods: The study aims to test for the first time in an international case study the multicriteria assessment tool previously developed and validated. The tool assesses social, environmental, and organisational qualities in hospitals with an online survey containing 199 closed questions sent to German hospitals. A total of 14 full replies have been collected and the resulting data analysed through descriptive statistics and heat maps identifying patterns in ownership and size. Results: Within the sample, higher scores are reported in Social Quality, while lower in Environmental and Organisational Quality. Respondents performed well in the sustainability dimensions of health promotion, waste management, and patient safety. Improvements can be achieved in energy management, facility management, and technological innovation criteria. Private hospitals slightly outperform both public and non-profit clinics. The findings presented in this study suggest a non-linear relationship between sustainability and hospital size since the highest scores were obtained by either small or large facilities. Conclusion: The study highlighted strengths and limitation of SustHealth v2. Further testing and comparison are encouraged in different context

Structural basis for specific inhibition of the deubiquitinase UCHL1

Ubiquitination regulates protein homeostasis and is tightly controlled by deubiquitinases (DUBs). Loss of the DUB UCHL1 leads to neurodegeneration, and its dysregulation promotes cancer metastasis and invasiveness. Small molecule probes for UCHL1 and DUBs in general could help investigate their function, yet specific inhibitors and structural information are rare. Here we report the potent and non-toxic chemogenomic pair of activity-based probes GK13S and GK16S for UCHL1. Biochemical characterization of GK13S demonstrates its stereoselective inhibition of cellular UCHL1. The crystal structure of UCHL1 in complex with GK13S shows the enzyme locked in a hybrid conformation of apo and Ubiquitin-bound states, which underlies its UCHL1-specificity within the UCH DUB family. Phenocopying a reported inactivating mutation of UCHL1 in mice, GK13S, but not GK16S, leads to reduced levels of monoubiquitin in a human glioblastoma cell line. Collectively, we introduce a set of structurally characterized, chemogenomic probes suitable for the cellular investigation of UCHL1